Abstract

The major function of the reproductive system is to ensure the survival of the species by passing on hereditary traits from one generation to the next. This is accomplished through the production of gametes and the generation of hormones that function in the maturation and regulation of the reproductive system. It is well established that normal development and function of the male reproductive system is mediated by endocrine and paracrine signaling pathways. Fibroblast growth factors (FGFs), their receptors (FGFRs), and signaling cascades have been implicated in a diverse range of cellular processes including: proliferation, apoptosis, cell survival, chemotaxis, cell adhesion, motility, and differentiation. The maintenance and regulation of correct FGF signaling is evident from human and mouse genetic studies which demonstrate that mutations leading to disruption of FGF signaling cause a variety of developmental disorders including dominant skeletal diseases, infertility, and cancer. Over the course of this review, we will provide evidence for differential expression of FGFs/FGFRs in the testis, male germ cells, the epididymis, the seminal vesicle, and the prostate. We will show that this signaling cascade has an important role in sperm development and maturation. Furthermore, we will demonstrate that FGF/FGFR signaling is essential for normal epididymal function and prostate development. To this end, we will provide evidence for the involvement of the FGF signaling system in the regulation and maintenance of the male reproductive system.

FGFR domain structure and isoforms generated by alternative splicing of FGFR transcripts. The main structural features of FGFRs are illustrated and include the signal peptide, the three Ig domains, acidic box, transmembrane domain, the JM domain/VT region and a split tyrosine kinase domain. The two forms of FGFR are generated by the alternative splicing of exons 8 and 9. The C-terminal portion of Ig domain III is encoded by exon 8 to generate the FGFR IIIb isoform, whereas the C-terminal portion of Ig domain III is encoded by exon 9 to generate the FGFR IIIc isoform (4,57,68,87,93).

Intracellular signaling activated through FGFRs. Formation of the FGF-Syndecan/heparin-FGFR complex leads to receptor autophosphorylation and activation of intracellular signaling cascades of the Ras/MAPK pathway, the PI3K/Akt pathway (left), and the PLCγ/Ca2+ /PKC pathway (right) (4,57,90,91). Syndecans facilitate the binding of FGFs to FGFRs, forming a ternary structure. EphA receptors induce tyrosine phosphorylation of FGFRs and FRS2 by forming a complex with the FGFR. The Ras/MAPK signaling cascade is activated by the binding of Grb2 to phosphorylated FRS2. The subsequent formation of the Grb2/SOS complex results in the activation of Ras. There are three routes by which FGFRs are able to activate the PI3K/Akt pathway: Gab1 can bind to FRS2 indirectly via Grb2, resulting in the tyrosine phosphorylation and activation of the PI3K/Akt pathway (2,96); PI3K can bind directly to a phosphorylated tyrosine residue of the FGFR (88); and lastly, activated Ras can induce membrane localization and activation of the PI3K catalytic subunit (57). The negative feedback signals that are mediated by or imposed on FRS2 are marked by the dotted line (94). The PLCγ/Ca2+ pathway is activated when autophosphorylation on a tyrosine residue in the carboxy terminal tail of the FGFR creates a specific binding site for the SH2 domain of PLCγ (91). The last activated components of the above-mentioned signal transduction cascades translocate into the nucleus and phosphorylate specific transcription factors of the Ets family, which in turn activate expression of FGF target genes. DAG, Diacylglycerol; IP3, inositol-1,4,5-triphosphate; SOS, son of sevenless.

Regulation of FGF signaling. The stimulation of FGFR by FGF ligands results in the activation of specific downstream target genes. Among the targets of the FGF signaling pathway are several feedback inhibitors, which are involved in the attenuation of FGF signaling and are part of the FGF synexpression group. Spry acts at the level of Grb2 and/or the level of Raf. Sef and XFLRT3 are both located at the membrane and can interact directly with FGFR. Sef functions as a negative regulator, whereas XFLRT3 enhances FGF signaling resulting in the phosphorylation of the MAPK ERK. Sef has also been shown to affect the phosphorylation of the MAPK cascade, either at the level of ERK or by preventing the phosphorylation of ERK by MEK (99). MKP3 negatively regulates FGF signaling by dephosphorylation of activated ERK. P, Phosphorylation. [Adapted from Ref. 43 with permission from Elsevier.]

Opposing signals regulate sex determination in the bipotential gonad. In both XX and XY gonads at 10.5–11.5 d postcoitum (dpc), Fgf9 transcripts (blue) are detected near the gonadal surface, whereas Wnt4 transcripts (pink) are detected near the gonad mesonephric boundary (123). At this time, in the bipotential gonad, there is a balance between these two competing signals. A genetic or environmental switch initiates the male pathway by creating an imbalance between these signals. Sry is activated in the XY gonad, and its expression diverts the XY gonad toward a testis-specific fate. Sry up-regulates Sox9, which has been implicated in the early steps of the male-specific pathway (121,123). Sox9 then up-regulates Fgf9, and Fgf9 (through FGFR2) maintains Sox9, forming a positive feedback loop in XY gonads (125). In this circumstance, the balance between FGF9 and Wnt4 signals is shifted in favor of FGF9, silencing Wnt4 signaling, and the dominance of the male pathway is established. In the absence of a feed-forward loop between SOX9 and FGF9 (e.g., in XX gonads), WNT4 suppresses Fgf9 transcription, initiating the female differentiation pathway.